Clinical Monograph for Drug Formulary Review: Systemic Agents for Psoriasis/Psoriatic Arthritis

BACKGROUND: Significant advances in the pharmacologic treatment of psoriasis,most notably the introduction of the biologic agents efalizumab and alefacept,have occurred recently. In addition, another biologic agent, etanercept, was recently approved for the treatment of psoriasis and psoriatic arthritis, thus adding to the list of biologic agents approved for the treatment of these disease states. A review was conducted by the Drug Information Service of a pharmacy benefits manager (PBM) to determine the relative merits and place in therapy of commonly used systemic agents for the treatment of psoriasis and psoriatic arthritis. OBJECTIVES: To provide readers with a comprehensive clinical monograph on psoriasis and psoriatic arthritis agents, written with a managed care perspective,as used in actual drug formulary decision making by a PBM. METHODS: The drug formulary of this PBM is designed to provide health plans with an evidence-based review of drugs, therapeutic classes, and disease states with a managed care focus. For each therapeutic class or disease review, an extensive and thorough literature search of MEDLINE is conducted for efficacy,safety, effectiveness, and humanistic and economic data. Drug/disease-state databases (UpToDate online, MICROMEDEX), U.S. Food and Drug Administration clinical reviews, key Internet sites, medical/pharmacy-related news sites, clinical guidelines, and AMCP dossiers are also reviewed. Formulary drug monographs produced by the Drug Information Service of the PBM include a critical analysis and summary of disease-oriented and patient-oriented clinical outcomes, effectiveness,and humanistic data. Additional data considered and included in the formulary review process are clinical attributes, patent expirations/generic competition, off-label or pending indications, and pharmacoeconomic data. RESULTS: The biologic agents do not appear to be as efficacious as traditional systemic therapies but are associated with fewer long-term toxicities that oftenlimit treatment duration with traditional systemic agents. Although no head-to head comparisons between alefacept and efalizumab exist, efalizumab appears to offer slightly higher efficacy rates, while alefacept has a longer duration of action. Etanercept at the higher approved dose appears more efficacious comparedwith efalizumab or alefacept for the treatment of psoriasis, and it is the only biologic currently approved for the treatment of psoriatic arthritis. Efalizumaband alefacept are generally well tolerated, but rebound flare of psoriasis associated with efalizumab, thus requiring continuous treatment to avoid a flare in disease. Efalizumab and etanercept can be self-administered by the patient, while alefacept and infliximab require administration by a health care professional. CONCLUSIONS: Systemic therapy is reserved for patients with moderate-to severe psoriasis or patients with psoriatic arthritis. The biologic agents are not as efficacious as traditional therapies but, due to better tolerability, are gaining acceptance in the treatment of psoriasis and psoriatic arthritis. The biologic agents differ in efficacy rates and are generally well tolerated. Clinical attributes,overall efficacy, and economic costs associated with the biologic agents will be significant factors in selecting agents for the treatment of psoriasis and psoriaticarthritis.


Evidence-Based Medicine Terms
spondylitis, and arthritis mutilans. Symmetric arthritis occurs in about half of psoriatic arthritis patients and can be disabling in about 50% of patients. Asymmetric arthritis is typically milder and occurs in about 35% of patients with psoriatic arthritis. 1 This monograph will give an overview of the systemic treatment options available for the most common type of psoriasis-plaque psoriasis-and for psoriatic arthritis, with a focus on the newest biological agents and their role in treating these conditions (Table 1). This review will include a critical analysis and summary of disease-oriented and patient-oriented clinical outcomes, effectiveness, and humanistic data ( Table 2).

ss II. Pathophysiology
Psoriasis and psoriatic arthritis are similar in that both diseases are immune-mediated chronic diseases with a genetic link. Psoriasis is caused by a hyperproliferative state, characterized by increased numbers of epidermal stem cells and numbers of cells undergoing DNA synthesis, keratinocytes undergoing a shortened cell cycle compared with normal skin (36 hours versus 311 hours), and a decrease in the turnover time of the epidermal skin layer compared with normal skin (4 days versus 27 days). 8 The presence of T lymphocytes and neutrophils in the epidermal and dermal layers, activation of growth factors (epidermal growth factor and transforming growth factor-alpha, and cytokines including interleukin-8 (IL-8), IL-6, IL-2, and interferon-gamma support immune regulation as a factor in psoriasis. 8 Psoriasis is characterized by patches of red, scaly, flaky skin that can be associated with intense itching and burning. Similar to psoriasis, psoriatic arthritis is linked to the presence of cytokines, including tumor necrosis factor (TNF)-alpha, IL-1beta, IL-2, IL-10, and interferon-gamma found to be present in the synovial tissue. 9 These cytokines stimulate the inflammatory process in the skin and synovium, thus leading to migration of activated T cells through the vascular endothelium causing leukocyte infiltration into the synovium. Activated T cells can also cause release of matrix metalloproteinases that cause joint damage. Historically, it was thought that psoriatic arthritis was not as debilitating or destructive a disease as rheumatoid arthritis, thus treatment was not as aggressive. However, recent data indicate that, because these patients have both psoriasis and psoriatic arthritis, they tend to report greater functional impairment. Thus, careful monitoring of patients with psoriasis is necessary to determine which patients may be developing psoriatic arthritis and which patients may require more aggressive therapy to prevent significant functional impairment. 9 It is not clearly defined which patients should be considered to have mild, moderate, or severe psoriasis, which is important in determining the optimal therapy for treatment. The National Psoriasis Foundation position paper provides some guidance in defining severity using QOL-based definitions in the absence of standardized criteria. 4 Table 3.)

ss III. Pharmacology/Pharmacokinetics Systemic Therapies Biologic Response Modifiers
Biologic response modifiers are the newest agents available for treating psoriasis and psoriatic arthritis. These agents differ in their mechanism of action ( Table 4). Efalizumab and infliximab are both humanized monoclonal antibodies, while alefacept and etanercept are dimeric fusion proteins. Pharmacokinetics of these agents differ from conventional therapies in that they require subcutaneous or intravenous administration, whereas

Mild
No alteration in patient QOL; patient can manage impact of disease and may not need treatment; treatments selected are not associated with any serious risks; BSA < 5%.

Moderate
Some alteration in patient QOL; patient requires therapy to improve QOL; treatments selected are associated with only minimal health risks in the short or long term; BSA = 2% to 20%.
Severe Alteration in patient QOL; disease unresponsive to treatments associated with minimal risks; patient is willing to accept lifealtering adverse effects to improve disease or clear disease; BSA > 10%. Also takes into consideration location of disease such as hands, feet, face; symptoms (pain, tightness, bleeding, or severe itching); presence of arthralgias or arthritis.

QOL = quality of life; BSA = body surface area.
Pharmacology of Biologic Response Modifiers [10][11][12][13]  Alefacept is a dimeric fusion protein consisting of the extracellular CD2binding portion of the LFA-3 that is linked to the Fc portion of IgG1. It works by inhibiting lymphocyte activation by binding to CD2 on T and NK cells. Decreases lymphocyte count (CD2 and memory cells). Studies have shown alefacept to exert greater effects on CD4+ memory cells, than CD4+ naïve cells. 14 Efalizumab is a recombinant humanized IgG1 monoclonal antibody that binds to the CD11a (subunit of the LFA-1) and prevents adhesion to ICAM-1, thus inhibiting T-cell activation and migration.
Etanercept is a dimeric fusion protein consisting of the extracellular ligandbinding portion of the TNF receptor linked to the Fc portion of IgG1. It exerts its effect by binding TNF and prevents interaction with cell surface TNF receptors, thus inhibiting the inflammatory process.
Infliximab is a humanized monoclonal antibody to TNF-alpha that neutralizes the activity of TNF-alpha, thus preventing induction of IL-1 and IL-6, inhibiting leukocyte migration, induction of acute phase reactants, and tissue-degrading enzymes. traditional agents are primarily administered orally.
In one study evaluating the pharmacokinetic/pharmacodynamic effects of alefacept, the Psoriasis Area Severity Assessment Index (PASI) and Physician Global Assessment (PGA) were correlated with increasing alefacept serum levels. 19 Dose-dependent decreases in peripheral CD4+ memory cells occurred during treatment with alefacept, which was shown to correlate with improvements in psoriasis. It is this specificity for reducing CD4+ memory cells that has been attributed to the sustained efficacy observed with this agent.
The pharmacokinetics of etanercept in treating psoriasis are similar to what is observed in patients treated with etanercept for rheumatoid arthritis. 20 The pharmacokinetics were similar whether patients were treated with 25 mg twice weekly or 50 mg once weekly, supporting that this dose would be efficacious in treating psoriasis patients. Long-term treatment was also shown to result in similar pharmacokinetics regardless of whether treatment was continuous or intermittent, thus suggesting the potential efficacy of etanercept when used in a sequential or rotational dosing scheme (Table 5). 21

Methotrexate
Methotrexate reduces the synthesis of tetrahydrofolate (by binding to dihydrofolate reductase) and subsequently inhibits pyrimidine synthesis. 15 These actions result in a reduction in DNA synthesis, inhibition of mitosis, and a decrease in the proliferation of rapidly dividing cells. Methotrexate is known to decrease T and B cell function and suppress the secretion of cytokines (IL-1, interferon-gamma, TNF).

Acitretin
Acitretin is an oral retinoid with anti-inflammatory, antiproliferative, and keratolytic activity. 15 Acitretin is the active metabolite of etretinate, previously known as Tegison. While etretinate takes years to be eliminated from the body, acitretin elimination takes several months. However, alcohol may precipitate conversion of acitretin back to etretinate, resulting in prolonged elimination. Because of the prolonged action of acitretin and teratogenic effects, women must avoid pregnancy during and for 3 years after discontinuing treatment. 16

Cyclosporine
Cyclosporine is an immunosuppressant that binds with the immunosuppressant-binding protein cyclophilin. 15 The immunosuppressive effects of cyclosporine result from the inhibition of cytokine promoters, which eventually inhibits the transcription and processing of cytokines (IL-2, interferon-gamma) within the T cells and decreases T-cell growth and migration. Cyclosporine absorption is variable and incomplete, although a newer emulsion formulation of cyclosporine has better absorption, at 43%. 17

Additional Agents
Several additional agents have been used in the treatment of psoriasis/psoriatic arthritis but are not U.S. Food and Drug Administration (FDA)-approved for these indications. Hydroxyurea is an antineoplastic agent that inhibits DNA synthesis, which slows basal cell replication in the epidermis. 15 Hydroxyurea also inhibits vascular proliferation in the dermis; lowers the neutrophil count, which decreases pustule and papule formation; and reverses abnormal keratin formation. Sulfasalazine is an anti-inflammatory agent that is thought to work by inhibiting prostaglandin synthesis and interfering with the arachidonic pathway. Azathioprine is an immunosuppressive agent that metabolizes to 6-mercaptopurine and inhibits DNA and RNA synthesis. 15 The mechanism of action of auranofin in treating psoriatic arthritis is unclear, but it is thought to work by reducing T-cell activity and inhibiting neutrophil migration. 18 Similarly, it is unclear how penicillamine exerts its effects in   22 The PASI is the most frequently encountered scale in the trials that follow and describes overall psoriasis severity and coverage, based on the amount of skin and degree of itching and scaliness involved in 4 defined body sections. A PASI75 is defined as a 75% improvement from baseline in PASI score and PASI50 is a 50% improvement in PASI score. Achievement of PASI50 is considered a clinically significant improvement. The PASI is a measure primarily used in clinical trials to demonstrate efficacy for FDA approval, but because it is both time-consuming to administer and complex, it is not commonly used in the clinical setting. New tools for measuring response are being developed that will take into consideration the effect on QOL in determining severity of disease and response to treatment. 23 Little information is available about recurrence or length of remission rates among various treatment approaches. The variable outcome measures should be considered when comparing outcomes from one trial to the next.

Treatment Strategies
A number of treatment options are available for treating psoriasis, both topical and systemic. Selection of treatment is dependent on the areas affected, type, severity level, and risk-to-benefit ratio of treatments. In general, first-line therapy for patients with mild disease consists of topical agents such as topical emollients, topical corticosteroids with or without coal tar, or calcipotriene. Second-line topical therapies include anthralin and tazarotene. For mild-to-moderate disease, low-to mid-potency corticosteroids are generally the first choice of therapy. 24 Usually, more potent corticosteroids, other topical agents, or systemic therapies are used for more severe disease or on areas of thicker skin. For thinner skin areas and for maintenance, a low-potency corticosteroid can be used. Low-potency products or noncorticosteroid agents are generally preferred in infants and elderly patients. 25,26 For patients with more severe disease that is unresponsive to topical therapies, systemic therapies are generally used.

Systemic Therapies for Psoriasis
For more severe disease unresponsive to topical agents or that involves large areas, phototherapy, with or without a topical agent or with methoxsalen, has been used. In addition, oral agents, such as acitretin, cyclosporine, and methotrexate, may be used as first-line therapy in patients with severe disease. Ultraviolet B (UVB) was considered a therapy of choice used alone or in combination with topical or oral agents; however, inconvenience and costs associated with this therapy have led to decreased use. 27 Psoralen plus ultraviolet A (PUVA) light is an effective therapy that has been shown to induce remission in patients; additional maintenance therapy adds to the high efficacy rates of 80% with this therapy. 28 However, long-term use can result in an increased risk of nonmelanoma and potentially melanoma skin cancer that may persist even after therapy is discontinued, which is a potential concern. 29,30 In addition, PUVA treatment can be inconvenient for the patient either because of a lack of availability of PUVA equipment in close proximity to the patient or because of a requirement for frequent treatments in the physician' s office. This may limit patient acceptance of this very effective therapy. PUVA is often combined with acitretin, an oral retinoid, to increase efficacy and decrease the amount of UVA energy required. 31 Combination therapy has been shown to be superior to PUVA alone, with clearance rates of 80% for PUVA compared with 96% with combination therapy, and was associated with a 42% reduction in the mean cumulative dose of UVA. 28 This combination is thought to potentially decrease toxicity and costs associated with use of either agent alone. 32 Spuls et al. conducted a systematic review of 5 systemic treatments for psoriasis. 33 A total of 665 studies involving systemic therapies-methotrexate, retinoids, cyclosporine, UVB, or PUVA-were identified. Patient series, focusing on treatment outcome, were used as the unit of analysis. After application of exclusion criteria, a total of 129 patient series (13,677 patients) were included in the analysis. The largest number of patient series evaluated PUVA; however, no studies on methotrexate remained in the analysis following exclusion. Two outcomes were evaluated-clearance and treatment response-defined as good (75% -100% improvement), moderate (50% -75% improvement), poor (< 50% improvement), and clearance (100% improvement). Good response was seen in 83% of patients treated with PUVA, 68% with UVB, 64% with cyclosporine, 56% with etretinate, and 56% with acitretin. The percentage of patients achieving clearing in each group was 70%, 44%, 13%, 22%, and 9%, respectively. The incidence of adverse events was also lowest with PUVA (0.6%). The authors suggested that phototherapy may be the first choice of systemic therapy for patients with severe psoriasis. A potential limitation of this review is that the exclusion rate was high due to concomitant use of other psoriasis agents, outdated dosages, or inadequate documentation in these studies. Of 821 patient series identified, 692 were excluded, for an inclusion rate of only 19%. This is primarily attributed to the fact that these agents have been used for many years, with many studies published as far back as 1958 for methotrexate, the 1970s for PUVA, and early 1980s to 1990s for many of the other agents; thus study design was not as stringent for the older agents.
In a systematic review by Griffiths et al., sufficient evidence from randomized controlled trials (RCTs) was identified to support the efficacy of cyclosporine, systemic retinoids in combination with PUVA, photochemotherapy, phototherapy, combinations of topical vitamin D3 analogues, and topical steroids in combination with photochemotherapy or phototherapy and fumarates. 34 In contrast, there was a lack of RCTs to support the use of methotrexate, hydroxyurea, azathioprine, and sulfasalazine. Because methotrexate was approved prior to requirement of RCTs for approval, limited RCTs are available.
Lebwohl et al. reviewed the use of cyclosporine in the treatment of psoriasis, concluding that it is best reserved for patients with severe psoriasis that have failed first-line therapies. 35 Typically, an induction dose up to 4 mg/kg/day (titrated) is used to treat a flare-up of psoriasis, then once the patient is clear or nearly clear of lesions, a lower maintenance dose can be used. In one study of 457 patients with severe psoriasis, treatment with cyclosporine 5 mg/kg/day resulted in 88% of patients achieving a 75% reduction in PASI (PASI75), with 52% of patients taking cyclosporine 2.5 to 3 mg/kg/day, and 24% of patients taking cyclosporine 1.25 mg/kg/day achieving PASI75 or greater. 36 Short-term, sequential, or rotational use is preferred because of potential risks associated with long-term therapy (renal toxicity and hypertension). For sequential or rotational therapy, cyclosporine is used to achieve remission, then patients are transitioned to acitretin for maintenance. 27 A recent comparative trial evaluated methotrexate and cyclosporine in patients with moderate-to-severe chronic plaque psoriasis, many of whom had failed topical, phototherapy, photochemotherapy, or acitretin. 37 Eighty-eight patients were randomized to methotrexate 15 mg/week titrated up to 22.5 mg/week or cyclosporine 3 mg/kg/day titrated up to 5 mg/kg/day if there was an inadequate response after 4 weeks of therapy. After 16 weeks of treatment, 40% of methotrexatetreated patients achieved a PASI90 compared with 33% of cyclosporine-treated patients, which was considered an almost complete remission. Partial remission or a PASI75 was achieved in 60% of methotrexate-treated patients compared with 71% of cyclosporine-treated patients. Duration of therapy was approximately 4 weeks for both treatments, indicating treatment must be continued for optimal effects. There was no significant difference in efficacy between agents, but more patients discontinued methotrexate (12 patients due to liver enzyme elevations) compared with only 1 patient discontinuing cyclosporine due to adverse effects.
Several small studies have shown hydroxyurea in doses of 0.5 grams to 1.5 grams per day to be efficacious in improving psoriasis in patients refractory to or failing conventional therapies. 38,39 Recently it was shown to be efficacious and safe in treating psoriasis in a patient with psoriatic arthritis when used in combination with infliximab. 40

Systemic Therapies for Psoriatic Arthritis
In a Cochrane Database Systematic Review of treatments for psoriatic arthritis, parenteral high-dose methotrexate and sulfasalazine were the two agents found to have the most data published demonstrating efficacy in treating psoriatic arthritis. 41 Of the 20 RCTs identified, 6 studies of sulfasalazine, 2 each of auranofin and etretinate, and 1 each of azathioprine, colchicine, fumaric acid, and low, pulse-dose methotrexate were included. A parenteral high-dose methotrexate study was also included. All agents were shown to be better than placebo, but only parenteral high-dose methotrexate, sulfasalazine, azathioprine, and etretinate reached statistical significance. It was also noted that patients receiving placebo improved over baseline, thus suggesting that noncontrolled trials are limited in their findings when evaluating treatments for psoriatic arthritis. The overall poor quality of studies limited the inclusion of studies and, thus, these findings.
Low-dose methotrexate (maximum 15 mg/week) was compared with cyclosporine (3 -5 mg/kg/day) in treating 35 patients with psoriatic arthritis. 42 Both agents significantly improved measures of disease activity-physician and patient assessments of disease activity at 6 and 12 months. More patients withdrew on cyclosporine therapy, while increases in liver enzymes were significantly more common with methotrexate, thus indicating the potential tolerability issues with each agent. In a study comparing cyclosporine (3 mg/kg/day) with sulfasalazine (2,000 mg/day) plus standard therapies or standard therapies alone (nonsteroidal anti-inflammatory drugs [NSAIDs], prednisone 5 mg/day, analgesics), cyclosporine was more efficacious overall compared with sulfasalazine or standard therapies, with only mild reversible kidney dysfunction reported more commonly with cyclosporine therapy. 43 Overall, sulfasalazine was superior to standard therapy alone in improving PASI, spondylitis functional index, and improved erythrocyte sedimentation rate but not in pain measures. Response to cyclosporine occurred at 8 weeks versus 34 weeks with sulfasalazine. In 3 studies evaluating the efficacy of sulfasalazine in treating psoriatic arthritis, although superior to placebo, efficacy was minimal, with high response rates reported in placebo patients. [44][45][46] Several small studies have evaluated the efficacy of auranofin (oral gold) and gold sodium thiomalate (injectable gold). [47][48][49][50][51] In general, the studies were small and not controlled, but results indicate that, while injectable gold is more potent in efficacy compared with oral gold, tolerability is better with oral gold. Data were not consistent across all studies, but, overall, they suggested superiority of gold compounds over placebo/control in improving symptoms of psoriatic arthritis. However, results of one study indicate gold compounds do not prevent progression of joint damage. 52 Data are limited regarding the safety and efficacy of antimalarial agents (chloroquine/hydroxychloroquine) or penicil- Study design: R, DB, PC trial in pts. with active psoriatic arthritis ( >3 swollen joints and >3 tender/painful joints and failed NSAIDs) and psoriasis (n = 60). Additional TXs allowed: (MTX < 25 mg/wk if stable for 4 wks, corticosteroids < prednisone 10 mg; stable NSAIDs therapy) Treatment(s): ETA 25 mg SC twice weekly or placebo for 12 weeks.

ss V. Humanistic Outcomes
The impact of psoriasis on patient QOL is well documented. 5 Several QOL measures have been used in assessing humanistic outcomes in psoriasis patients, including the Dermatology Life Quality Index (DLQI), PDI, and the Short-Form 36 Health Survey (SF-36). The DQLI is commonly used, but it is a general measure for dermatologic QOL. Thus, a new QOL instrument is being developed and validated that is specific to psoriasis, the Psoriasis Quality of Life Questionnaire, which should help differentiate between levels of disease severity and clinically important improvements with topical and systemic therapies. 5 Several studies have evaluated improvements in QOL associated with the newest biologic agents.

Alefacept
Significant improvements in HRQOL were noted in 229 patients with moderate-to-severe psoriasis treated with alefacept. 81 Patients treated with alefacept administered intravenously experienced significantly greater improvements in dermatology-specific QOL measures compared with patients treated with placebo. Significant improvements in the DLQI and the Dermatology Quality of Life Scales (DQOLS) were Study design (n): R, DB, PC, MC trial in pts. with moderate-to-severe chronic plaque psoriasis (>1 year and BSA >10%), age > 18 years, who were candidates for phototherapy or systemic therapy (n = 507). Treatment(s)*: ALE 10 mg, ALE 15 mg, or placebo IM once weekly for 12 weeks, then followed up for 12 weeks.

Placebo-Controlled Trials of Biologic Agents for the Treatment of Psoriasis
OUTCOMES: Primary end point: % pts. with PASI75 or greater at 2 weeks post-TX was 21% with ALE 15 mg vs. 5% with placebo (P<.001; NNT=6). Overall response after TX course 1: PASI75 or greater 33% with ALE 15 mg and 28% with ALE 10 mg vs. 13% with placebo (P<.001; NNT=5-7); PASI50 or greater 57% with ALE 15 mg and 53% with ALE 10 mg vs. 35% with placebo (P<.001 and P=.002), respectively; NNT=5-6); PGA clear/almost clear 24% with ALE 15 mg and 22% with ALE 10 mg vs. 8% with placebo (P<.001; NNT=6-7). Tolerability: Overall, ALE was well tolerated, with headache (typically single event) and mild injection site reactions (pain, pruritis, and inflammation-mild, transient that did not cause withdrawal from study) reported most commonly. No significant infections, reductions in CD4+ counts, serious drug-related AEs, or increases in malignancy were noted. AST elevations up to 3 times the ULN were noted in 8%-13% of ALE pts. vs. 9% in placebo pts., primarily in pts. with a history of hepatic illness or taking hepatotoxic drugs. No other alterations in liver function were noted. Antialefacept antibodies detected in 4% (14) pts., but were low titers, did not increase, and were not neutralizing.
Comments: Similar baseline characteristics, median duration of disease was 19 years (range 2-77 years); median BSA 21%. Pts. with more severe disease and pts. with no prior history of systemic therapy had higher response rates.

Krueger et al., 2002 58
Study design (n): R, DB, PC, MC trial in pts. with chronic plaque psoriasis (>1 year and BSA >10%), age >16 years, who were candidates for phototherapy or systemic therapy (n=553). Treatment(s): ALE 7.5 mg IV once weekly for 12 weeks then placebo for 12 weeks, ALE 7.5 mg IV once weekly for two 12 week courses, or placebo for 12 weeks, then ALE 7.5 mg IV once weekly for 12 weeks. There was a 12-week TX-free follow-up period after each TX course. Additional TXs allowed: lowpotency corticosteroids allowed, but not for 12 hours before efficacy evaluation; moderate-potency corticosteroids; vitamin D analogs; topical retinoids; keratolytics; and coal tar allowed on groin, scalp, palms, and soles only. . Duration of response: Pts. achieving PASI75 during or after TX, without phototherapy or systemic therapy, maintained PASI 50 or greater for 7 months (216 days) following 1 course of TX and beyond 48 weeks (379 days) for pts. following 2 courses of TX. Tolerability: Chills occurred more commonly with ALE, which occurs within 24 hours of dose and decreased with a subsequent course of therapy. Increased ALT < 3 times normal occurred more commonly with ALE vs. placebo (17% vs. 8%) with second course of TX, but mild with no other alterations in liver function. Dose reduction required in 10% of ALE pts. due to increased CD4+ lymphocyte counts. Antialefacept antibodies detected in < 1% (n = 5) of pts.
Comments: No cases of rebound or flare of psoriasis were observed after ALE TX ended. Improvements in PASI and PGA were correlated with increasing ALE serum levels. Dose-dependent decreases in CD4+ memory cells were noted. Dose-dependent decreases in CD4+ memory and naïve cells were correlated with improvements in psoriasis. Primary objective was to evaluate the remission period following TX with ALE. Of the 148 pts. completing TX with ALE, 118 (80%) required no additional TX for up to 3 months after stopping therapy. Of the 118 pts., 16 pts. were clear or almost clear for 3 months post-TX. Twenty-six of the ALE pts. subsequently were treated with a second course of ALE. Pts. did not require re-TX for several months, with a mean time between TXs of 10 months (range 6-18 mos).

Comments:
This study suggests a long duration of efficacy with ALE TX.

Lowe et al., 2003 60
Interim report of ongoing trial: OL, MC, re-TX study in pts. previously treated in Phase II trials with ALE or placebo, requiring additional systemic TX. Treatment(s): ALE 7.5 mg IV bolus once weekly for 12 weeks. Re-TX course 1 (n=170), Re-TX course 2 (n=50). Additional TXs allowed after wash-out period: low-potency corticosteroids allowed, but not for 12 hours before efficacy evaluation; moderate-potency corticosteroids, vitamin D analogs, topical retinoids, keratolytics, and coal tar allowed on groin, scalp, palms, and soles only.
OUTCOMES: Re-TX course 1: % of pts. achieving overall response-PGA of clear or almost clear 29%, PASI75 or greater 39%, PASI 50 or greater 66%. Re-TX course 2: response rates for PASI75 were higher compared with course 1, pts.' baseline measures were lower than before course 1, indicating some retention of effects. Tolerability: AEs were similar to those seen in previous TX courses, with pharyngitis and rhinitis the most common reported AEs. No complicated infections were reported. TX discontinuation occurred in 3 pts. due to low CD4+ t-cell counts. Five pts. with a positive family or medical history of risks for cancer were diagnosed with cancer (1 colon, 1 lung, 3 skin cancer). 1.7% (3/174) of pts. tested positive for antialefacept antibodies, but titers were low and not associated with AEs.
Comments: Pharmacodynamic data showed selectivity for CD4+ memory cells over CD4+ naïve cells. Additional data are being collected in pts. receiving a third re-TX course.  . Improvements in PGA were significantly better in all ETA groups vs. placebo at week 12. Tolerability: ETA was well tolerated with similar incidence of AEs and infections across all groups. Eight ETA pts had non-neutralizing ETA antibodies, with no difference in efficacy or safety noted. Study design: Follow-up extension of above study (of 652 pts., 409 pts. were responders and entered withdrawal period).

Treatment(s):
Active-treatment pts. were withdrawn from study drug after 24 weeks and followed for relapse.  Study design: Pooled analysis of data from 2 phase 3 trials (n = 1,235). Treatment(s): ETA 50 mg twice weekly, ETA 25 mg twice weekly, 25 mg once weekly for 24 weeks or placebo for 12 weeks followed by ETA 25 mg twice weekly for 24 weeks.

Placebo-Controlled Trials of Biologic Agents for the Treatment of Psoriasis
OUTCOMES: End point-% pts. that were nonresponders at week 4 that went on to become responders with continued treatment: Of pts. who were not responders at week 4: 33% of 25 mg twice-weekly and 53% of 50 mg twice weekly pts. achieved PASI50 by week 8. Of pts. who were not responders at 4 weeks: those that became responders at 12 weeks were 51% for 25 mg twice weekly and 67% for 50 mg twice weekly.
Comments: Improvements have been reported beginning at 2 weeks; however, these data indicate response can increase in nonresponders following 3 months of therapy. Limitation: Poster presentation, statistical significance not stated, full study not published. Comments: Statistically significant improvements in PASI began at week 8, PGA at week 4, and Patient Global Score at week 2.

Elewski et al., 2004 67 [poster]
Study design: MC, DB, R trial in pts. with stable plaque psoriasis (BSA > 10%, trial of at least one systemic therapy or a candidate for systemic therapy) (n=583).

Treatment(s):
ETA 50 mg twice weekly for 12 weeks then 25 mg twice weekly (step-down) for 12 weeks, ETA 25 mg twice weekly for 24 weeks, or placebo for 12 weeks followed by ETA 25 mg twice weekly for 12 weeks.

Comments:
Step-down dosing showed similar efficacy to that observed in 50 mg twice weekly dosing in study by Leonardi et al., 2003. Additional one third of pts. not responding on 50 mg twice weekly did go on to respond even following step-down dosing to 25 mg twice weekly. P-values were not provided to determine statistical significance.
Comments: Mean PASI at baseline was 20, mean duration of psoriasis was 19 years, 67% of pts. had received previous TX with systemic therapy. Significant difference in efficacy was noted at week 4 of TX with EFA vs. placebo. This study did not evaluate PGA of improvement. The 2 mg/kg/wk and 4 mg/kg/wk doses are higher than the FDA-recommended dose of 1 mg/kg/wk. There were no statistically significant differences in efficacy between the 1 mg/kg/wk and the 2 mg/kg/wk doses. Of pts. who achieved PASI75 with EFA during the initial 12 weeks and were then switched to placebo, only 20% maintained that improvement at week 24 vs. 77% of pts. who continued with EFA treatment. At week 24, relapse (50% or more loss in improvement) occurred in 8% of pts. who continued on EFA and in 67% of pts. who discontinued EFA therapy after 12 wks.  Study design: R, DB, PC, MC trial in pts. with moderate-to-severe plaque psoriasis (PASI of >12, BSA>10%, candidate for systemic therapy) (n=556) Additional TXs allowed: Emollients, tar or salicylic acid agents for scalp, limited application of low-potency corticosteroids for face, hands, feet, groin, and axillae. Treatment(s): EFA 0.7 mg/kg/wk or placebo times one dose, followed by 1 mg/kg/wk or placebo for 11 weeks.
Comments: Logistic regression analysis did not show a difference in efficacy based on baseline PASI score, age, sex, or history of prior systemic therapy. Onset of response occurred at 4 weeks, but duration of response was not measured in this study.
OUTCOMES: % pts. achieving a 50% or better PGA at 8 weeks: EFA 0.3 mg/kg/wk 48% vs. placebo 15% (P=.002). 25% of EFA 0.3 mg/kg/wk pts. had > 75% improvement in PGA vs. 2% with placebo (P=.0003). Epidermal thickness was reduced with EFA 0.3 mg/kg/wk 37% vs. placebo 19% (P=.004). Tolerability: EFA was well tolerated, AEs were primarily flu-like symptoms that occurred with the first dose and then decreased with subsequent doses. Transient increases in white blood cell and lymphocyte counts were noted.  Clinical Monograph for Drug Formulary Review: Systemic Agents for Psoriasis/Psoriatic Arthritis observed in patients who experienced a 50% or 75% improvement in PASI at 12 weeks compared with patients treated with placebo (P <.05). The general QOL survey (SF-36) was found to be less specific in determining QOL in these patients. Similar results were noted in 509 patients with moderate-to-severe chronic plaque psoriasis who were treated with alefacept 15 mg administered intra-muscularly. 82 At 12 weeks, patients treated with alefacept experienced statistically significant improvements in DLQI, DQOLS, and SF-36 compared with patients treated with placebo.

Efalizumab
Efalizumab was shown to improve DLQI scores in a pooled analysis of 2 phase III studies. 83,84 QOL was assessed in 1,095 patients with moderate-to-severe psoriasis treated with efalizumab or placebo. DLQI scores decreased from 12 to 6 with efalizumab 1-2 mg/kg/wk compared with an improvement from 12 to 10 with placebo. Similar results were shown in a phase III trial in 556 patients with moderate-to-severe psoriasis. 69 Significantly greater improvements were reported with efalizumab-treatment compared with placebo treatment at 12 weeks (47% versus 14%; P<.001). Significant improvements were noted in the efalizumab-treated patients beginning at week 4 and were consistent across all DLQI components, with the greatest improvements in the symptoms and feelings sections. Additional analyses showed the greatest improvements in DLQI were observed in patients achieving a PASI50.

Etanercept
In a follow-up to the study by Mease  OUTCOMES: PASI scores improved by approximately 50% in all pts. Pts. with psoriatic arthritis experienced a moderate-to-major improvement in arthritis. Combination therapy was well tolerated with no significant AEs reported.
Limitations: Uncontrolled case-series study. Time frame for response not stated in all pts., 2 pts. showed improvements within 5-8 weeks. Comments: Case series provides low evidence, due to small size and lack of controls.

Antoni et al., 1999 78 [abstract]
Study design: OL trial in pts. with severe psoriatic arthritis failing MTX therapy (n = 6). Additional TX allowed: NSAIDs, MTX, steroids. Questionnaire scores, with an improvement of 0.6 units compared with a 0.1 unit improvement with placebo (54% versus 7%; P <.001). An improvement of 0.22 units is considered clinically significant. Similarly, a significant improvement in the Medical Outcomes Study SF-36 scores was observed with etanercept compared with placebo (mean change of 9.3 versus 0.7 with placebo; P <.001). This was primarily attributed to improvements in the Physical Component Summary with a trend toward improvement in the Mental Component Summary, which did not reach statistical significance. A significant improvement in the EuroQOL Feeling Thermometer, which is a multidimensional measure of HRQOL, was reported with etanercept compared with placebo (mean improvement of 14.3 units versus 2.1 units; P <.001).

ss VI. Pharmacoeconomics
In an economic study published by Feldman et al., methotrexate was the least costly treatment at $1,600 annually, followed by phototherapy $3,600, PUVA $4,600, acitretin $5,200, cyclosporine $6,500 to $10,000 (3 -5 mg/kg/day), alefacept $16,000 to $20,000 (1.5 courses/year-assumes intravenous [IV] administration, labs tests and office visits), and etanercept $16,900 to $33,000 (25 mg twice weekly -50 mg twice weekly). 27 Assumptions included costs of laboratory tests, office visits, and drug acquisition costs (average wholesale price) but did not include costs associated with rare adverse events. The analysis also included assessment of the cost per treatment success based on efficacy from published studies but not from headto-head comparisons. Methotrexate remained the least costly therapy at $5,400; both UVB and PUVA had similar costs per treatment at $5,100 to $5,700, while costs per treatment were somewhat higher for cyclosporine (5 mg/kg/day) at $14,200 and acitretin monotherapy at $17,300. However, costs per treatment with the biologic agents were higher than the traditional therapies at $35,900-$40,600 annually for etanercept (25 mg twice weekly -50 mg twice weekly). Infliximab costs per treatment were lower at $22,500 for 5 mg/kg (6 infusions) but were based on a high efficacy rate of 80% noted in a single trial.
In a decision-analytic model by Chiou et al, the cost-efficacy of biologics was compared in treating psoriasis. 85 Data were based on package insert information and published clinical trial data that were then reviewed by an expert panel of dermatologists. The analysis was conducted from a managed care perspective and was evaluated over a 6-month period, based on efficacy at 12 to 14 weeks that was assumed to be maintained at 6 months. Costs included drug costs, laboratory monitoring, and costs of treating moderate-to-severe adverse events. Costs of therapy over 6 months were $13,342 for alefacept (dosed for 12 weeks); $11,295 for efalizumab; $9,781 for etanercept (25 mg twice weekly); $14,273 for etanercept step-down dosing (50 mg twice weekly for 12 weeks, then 25 mg twice weekly for 12 weeks); and $18,600 for etanercept 50 mg twice weekly. However, additional analyses of incremental cost-efficacy showed etanercept to be the most cost-effective agent because of higher efficacy rates. Limitations included lack of head-to-head data and use of expert opinion to classify adverse events. It should be noted that the study was supported by a grant from Immunex/Amgen, the manufacturer of Enbrel (etanercept).
Additional useful measures of the costs associated with use of biologic agents would be to calculate cost per day of response to therapy or the cost of treatment failure compared with conventional therapies or other biologic agents. See Table 9 for sample annual costs for 1 year of treatment for psoriasis or psoriatic arthritis.

ss VII. Adverse Effects
Many of the systemic agents used in treating psoriasis and psoriatic arthritis work by affecting the immune system, thus causing concern over their long-term use and the potential for an increased risk of infection. The commonly reported adverse effects associated with conventional systemic therapies for psoriasis are provided in Table 10. These data highlight the safety and toxicity issues associated with these therapies that have led to development and increased utilization of biologic agents.

Alefacept
The most common adverse effects reported with alefacept were chills, dizziness, nausea, increased cough, and injection site pain. 10 Serious adverse effects were uncommon but included lymphopenia (dose-dependent reductions in CD4+ and CD8+ counts), which accounted for 4% of patients receiving intra-  Clinical Monograph for Drug Formulary Review: Systemic Agents for Psoriasis/Psoriatic Arthritis muscular injections to temporarily discontinue therapy. Subsequent courses resulted in a higher portion of patients experiencing below-normal counts. 86 Data also showed a higher incidence of serious infections requiring hospitalization compared with placebo (0.9% versus 0.2%), which increased with subsequent courses (1%). Maximum effects on lymphocyte counts were observed at 6 to 8 weeks after initiation of therapy. The incidence of malignancy was also slightly higher with alefacept, with 1.3% of patients diagnosed compared with 0.5% of patients in the placebo group. The majority of cases were basal or squamous cell cancers, but 3 cases of lymphoma were reported. There were rare reports of increased transaminase levels 5 to 10 times the upper limit of normal (9 patients) during clinical trials. 10

Efalizumab
Serious infections occurred in 0.4% of efalizumab-treated patients and 0.1% of placebo-treated patients during the initial 12 weeks of therapy. 12 The risk of malignancy with efalizumab is not known, but because it is an immunosuppressive therapy, patients should be monitored for malignancy or the drug discontinued in patients diagnosed with a malignancy. Severe thrombocytopenia occurred in patients during clinical trials, with 0.3% of efalizumab-patients experiencing thrombocytopenia (platelet counts below 52,000 cell/mcL) compared with no cases reported with placebo. In 3 of the 8 patients experiencing severe thrombocytopenia, all cases were consistent with an immune-mediated reaction. Worsening of psoriasis occurred in 0.7% (19 patients) of efalizumab-treated patients, with most cases occurring after discontinuation of therapy. Some cases were severe and required hospitalization (17 of 19 patients) or alternative psoriasis therapy, with conversion to psoriatic erythroderma and pustular psoriasis reported in some patients. The rate of psoriasis adverse events, including both nonserious and serious cases, observed during placebo-controlled trials was 3.2% (52 of 1,620) with efalizumab compared with 1.4% (10 of 715) with placebo. 12 Recent analysis of safety data from 13 clinical trials in 2,762 patients showed 13.8% of efalizumab-treated patients experienced psoriasis that returned to worse than baseline with discontinuation of therapy compared with 11.1% of patients. 87 First-dose reactions of headache, fever, nausea, and vomiting occur with efalizumab, which are dose-related; thus, an initial lower conditioning dose is recommended. Hypersensitivity reactions were uncommon but occurred more commonly with efalizumab compared with placebo (1% versus 0.4%). Inflammatory/immune-mediated reactions occurred in 0.5% of patients treated with efalizumab, including 2 cases of interstitial pneumonitis. Elevations in alkaline phosphatase occurred more frequently with efalizumab compared with placebo (4% versus 0.6%), and the percentage of patients with above-normal liver function tests was also higher with efalizumab compared with placebo (3.1% versus 1.5%). Long-term immunogenicity of efalizumab is not known; however, 6.3% of patients developed antibodies to efalizumab.

Etanercept
The most frequent adverse event is injection site reactions (37%). 11 Injection site reactions tend to decrease in severity over time. Recently published data analyzing safety from 1 phase II and 2 phase III trials showed the incidence of injection site reactions was lower than observed in rheumatoid arthritis trials. 88 The incidence of infections overall was low, at less than 1% with no reports of conversion of psoriasis to other types. Etanercept has been associated with rare postmarketing reports of pancytopenia, including aplastic anemia, although a causal relationship has not been established. 11 Caution is advised for use in patients with a history of significant hematologic abnormalities. Treatment with etanercept and other agents with similar mechanisms of action have been associated with rare reports of new onset of demyelinating disease such as multiple  [10][11][12][13][16][17][18][92][93] sclerosis, and exacerbations of preexisting disease. Caution is advised when prescribing etanercept in patients with preexisting disease. Adverse events with etanercept treatment in pediatric patients are similar in frequency and type as those seen in adult patients. Non-neutralizing antibodies to etanercept have been reported in clinical studies, but no correlation to clinical response or adverse events was noted. Analysis of clinical trials in psoriasis patients showed a 6% incidence of antietanercept antibodies, although titers were low and antibodies were non-neutralizing with no apparent effects on safety or efficacy. 88

Infliximab
Safety of infliximab is based on data from clinical trials in rheumatoid arthritis. Safety data for treatment of psoriasis have not been fully elucidated in large well-controlled trials. Similar to etanercept, demyelinating syndromes have been associated with infliximab. Use should be avoided in patients with preexisting multiple sclerosis. 13 Efficacy with infliximab is more durably sustained when combined with methotrexate in treating rheumatoid arthritis. Data are not available to clarify if infliximab should be administered only in combination with methotrexate for psoriasis and psoriatic arthritis, but in preliminary studies, it was often used in combination with other agents, including methotrexate.

Congestive Heart Failure With Infliximab or Etanercept
During clinical trials evaluating the efficacy of etanercept and infliximab in patients with congestive heart failure (CHF), it was determined that these agents may not improve CHF and could decrease survival. 89,90 Two phase II studies with etanercept (RENAISSANCE and RECOVER) were stopped early due to lack of efficacy and an increased incidence of worse outcomes in patients in one study. During the postmarketing period, cases of worsening heart failure have been reported in patients treated with etanercept in both patients with and without precipitating factors. 11 In the ATTACH trial, infliximab was shown to increase the risk of mortality or worsen CHF; thus, this agent is contraindicated in patients with CHF. For CHF patients already on infliximab therapy, infliximab should be discontinued in patients whose CHF is worsening, and discontinuation should be considered in patients with stable concomitant CHF. Current labeling contraindicates use of infliximab in patients with moderate-to-severe CHF and cautions use of etanercept in patients with CHF. The FDA and manufacturers of these products are conducting ongoing surveillance of the risk of CHF with these agents. 91 ss VIII. Drug/Food Interaction Formal drug/food interaction studies have not been conducted with the biologic response modifiers. However, drug interactions are minimal compared with conventional therapies.
A summary of food/drug interactions with systemic therapies is presented in Table 11.
No formal drug interaction studies have been performed with alefacept, and the optimal time period between initiating other therapies following use of alefacept is not known. 10 The safety and efficacy of administering live or live-attenuated vaccines with alefacept have not been fully evaluated. However, the effects of alefacept on the immune response were specifically evaluated in a randomized, controlled, open-label trial in 46 patients with chronic plaque psoriasis. 94 Patients were randomized to treatment with alefacept 7.5 mg IV once weekly for 12 weeks or to a control group. Patients were then exposed to an antigen as well as to a recall antigen (tetanus toxic) to determine if there was a significant difference in the immune response between patients treated with alefacept or who were in the control group. Results showed similar mean antibody titers to both the antigen and tetanus toxic, thus suggesting that alefacept selectively inhibits T cells, allowing patients to retain a significant immune response to fight infection or to be able to respond appropriately to vaccinations. Conversely, although www Table 12.
FDA-approved dosing recommendations and a summary of patent information are presented in Table 13.

ss X. Conclusions
Psoriasis is a chronic skin condition that varies in extent and severity. The majority of patients have mild-to-moderate disease with approximately 30% of patients progressing to moderateto-severe psoriasis. In general, the disease is not life-threatening, but for patients with more severe disease, it can greatly impact QOL. The goal in treating plaque psoriasis is to obtain rapid control and maintain such, which includes drug therapy with minimal adverse effects as well as a planned approach to address psychosocial implications of the disease. The approach to treatment is variable and dependent on the type of psoriasis, the extent of the disease, and the areas of involvement. The mainstay of therapy for localized disease is topical corticosteroids, calcipotriene, coal tar, tazarotene, and anthralin, while systemic therapy is usually reserved for generalized and more severe disease. For patients with progressive disease despite the aforementioned topical therapies, phototherapy (PUVA) can be used with or without a topical agent. Adjunctive therapy with emollients free of lactic acid or alpha-hydroxy acids can hasten lesion resolution with any of the treatments and should be encouraged. Systemic therapy-acitretin, methotrexate, cyclosporine, infliximab, efalizumab, alefacept, etanerceptshould be reserved for patients with moderate-to-severe generalized disease. Furthermore, because of the potentially serious adverse effects associated with some of these agents, rotational therapy may be needed. The American Academy of Dermatology is in the process of updating the evidence-based guidelines on the treatment of psoriasis published in 1991 and recently published a consensus statement on treatment to provide guidance in the interim. 99 The statement suggests that selection of therapy include the following considerations: type of psoriasis; location of lesions; severity of the lesions, specifically thickness, redness, scaling; extent of the disease based on BSA or PASI score; age of the patient; symptoms, including pain and pruritis; response to previous therapies; accessibility to a dermatologist or ultraviolet light facility; physician preferences; economic factors; cost/ benefit ratios; quality of life, specifically the ability to perform daily activities; employability; and interpersonal relationships. Additional considerations are comorbid diseases that may limit or affect treatment options, such as liver disease, hepatitis C, HIV infection, hypertension, and alcohol intake. Consideration must also be given to child-bearing potential, pregnancy, desire to become pregnant, and desire to impregnate.
Mild disease includes patients with limited BSA involvement and, with selection based on severity and location of lesions, is generally responsive to topical therapies such as topical corticosteroids, tazarotene, calcipotriene, anthralin, tar preparations, salicylic acid, lactic acid, urea, lubrication products, or combinations of these agents.
Moderate-to-severe disease generally includes patients with BSA > 10%, but patients with lower BSA involvement may be classified as moderate-to-severe if the palms, soles, head and neck, or genitalia are involved. These patients usually have more generalized or severe disease that is unresponsive to topical agents alone, thus prompting use of systemic therapies. Phototherapy (UVB with or without topicals) or photochemotherapy (PUVA) with or without oral retinoids may be a first option for systemic therapy, depending on the availability of light facilities. Methotrexate and cyclosporine have similar efficacy and are alternative choices; often these agents are used in a rotational or sequential method to avoid toxicities observed with long-term use. For more chronic use, methotrexate may be preferred over cyclosporine since chronic use of this agent is typically limited to 1 year in duration. Acitretin, an oral retinoid, can be used alone, but it is also used in combination with phototherapy or photochemotherapy to reduce the doses required and decrease toxicity of light therapy.
The newer biologic agents, efalizumab and alefacept, are potential options, as is infliximab, which has shown some efficacy in psoriasis, although published data are currently limited. Etanercept was recently approved for psoriasis and has published data to support efficacy and safety. Notably, dosing is higher with etanercept for treating psoriasis than for the other approved indications. Thus, cost will be higher with the initially higher dose, but will be comparable with other biologics when the dose is reduced to the typical dose after the first 3 months of therapy. One economic analysis showed that step-down dosing with etanercept, which is the approved dose, was higher than efalizumab and alefacept at 6 months. However, based on a higher efficacy rate, it was deemed the most cost-effective agent, although this was not based on head-to-head trials.
In addition to this guidance, additional considerations are that long-term data are not available with the biologic response modifiers. Exceptions are that long-term data are available with etanercept and infliximab in treating other conditions. Biologic agents do appear less efficacious compared with methotrexate and cyclosporine, but they may be less toxic in the long-term. Other differences in systemic therapies that must be compared include onset of action and ease of administration. Alefacept has ROUTINE MONITORING: CBC with platelet counts, urinalysis, and body temperature every 2 weeks for 6 months. LFT every 6 months. Special consideration: Pregnancy category D.   Patent issues: Because of the complexity of producing biologic proteins, the potential for immunogenicity, safety concerns, and the ability to produce therapeutically equivalent generic products, it is unclear when or if generic biological agents will become available. The FDA is currently reviewing and trying to develop guidelines for approval and development of generic biological agents. [97][98] No patents or exclusivity are remaining on the other products listed. Clinical Monograph for Drug Formulary Review: Systemic Agents for Psoriasis/Psoriatic Arthritis a slower onset of action compared with efalizumab, with a longer duration of activity. Efalizumab must be administered in a continuous fashion to maintain efficacy and to prevent loss of efficacy or a flare in disease, but it has a faster onset of action. Alefacept must be administered intramuscularly by a health care professional and requires weekly CD4 counts, while efalizumab can be administered subcutaneously by the patient and requires only monthly monitoring for thrombocytopenia. Etanercept can be self-administered, has not shown flare of disease with discontinuation, and is also FDA-approved for the treatment of psoriatic arthritis. An additional consideration is the high cost of the biologic agents in comparison with conventional therapies used to treat psoriasis. The overall value of these agents in treating this chronic relapsing and remitting condition must be considered when selecting appropriate therapy. The biologic agents would best be used in patients with moderate-to-severe psoriasis who have failed or are not candidates for other systemic therapies. (See Table 14).
First-line treatment of psoriatic arthritis focuses on the use of NSAIDs, particularly for patients with mild disease activity. 9 It should be noted that the use of NSAIDs may exacerbate psoriasis. Patients with more severe disease who are unresponsive to NSAID therapy should be treated with disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, sulfasalazine, and cyclosporine. Intra-articular injections of corticosteroids may be a therapeutic option in patients with limited disease in only one or two joints, but systemic use of corticosteroids is not recommended. For patients unable to tolerate DMARDs, biologic agents, such as etanercept and infliximab, are efficacious and safe. For patients with psoriatic arthritis with spinal involvement such as spondylitis, biologic agents may be used more as a first-line therapy compared with other forms such as DIP, symmetric disease, or asymmetric disease, which primarily affects joints in the hands and feet.
However, safety and efficacy of the biologic agents in the longterm treatment of psoriatic arthritis are not available.
Author' s Note: As part of the formulary review process, we provide P&T committee members with a summary of available data on the agents under review (see Table 15, page 52) in addition to the full clinical monograph. This table is designed to highlight key points pertinent to the decision criteria the committee uses to decide product formulary status, including effectiveness and efficacy outcomes, safety, and clinical attributes. Cost is considered only if all other decision criteria are similar and it provides a differentiation point in determining the value of the products under review.

ACKNOWLEDGMENTS
The author would like to acknowledge the assistance of Craig Leonardi, MD, clinical assistant professor of dermatology, St. Louis University Medical School, St. Louis, Missouri, and Glenn Ehresmann, MD, associate professor of clinical medicine, Division of Rheumatology, University of Southern California School of Medicine, Los Angeles, for their time and assistance with review of the original monograph and development of the place-in-therapy criteria.

DISCLOSURES
No outside funding supported this study. The author discloses no potential bias or conflict of interest relating to this article.

Place-in-Therapy Recommendation for Amevive, Raptiva, and Enbrel for the Treatment of Psoriasis
Criteria for use: • Age > 18 years • Diagnosis of moderate-to-severe plaque psoriasis with BSA > 10% and a candidate for systemic or phototherapy. Patients with BSA < 10% may be candidates for systemic or phototherapy if they have involvement of the palms, soles, head and neck, or genitalia that is considered to be moderate-to-severe disease. In addition, the patient must meet at least ONE of the following: • Failure on one or more of the following treatments: phototherapy, photochemotherapy, acitretin, methotrexate, cyclosporine, or another biologic therapy

Place-in-Therapy Recommendation for Enbrel for the Treatment of Psoriatic Arthritis
Criteria for use: • Age > 18 years In addition, the patient must meet at least ONE of the following: • Psoriatic arthritis with spondylitis (spine involvement) • Psoriatic arthritis with history of previous trial/failure or intolerance to disease-modifying anti-rheumatic agents, specifically methotrexate or sulfasalazine BSA = body surface area.